One of the major characteristics of human immunodeficiency virus (HIV) infection is the intense degree of cellular activtion that occurs throughout the course of HIV disease. Cellular activation plays a major role in the pathogenesis of HIV disease since HIV replicates much more efficiently and spreads more readily among activated cells. In addition, persistent immune activation contributes to the immune defects in HIV infection by inducing anergy and/or apoptosis among activated cells. We have investigated the immunopathogenic mechanisms responsible for CD4+ T-cell depletion in HIV infection and the role of cellular activation in this process. Apoptosis is 3- to 4-fold higher in lymph nodes of HIV-infected individuals compared to those of HIV-uninfected individuals. Generally, all compartments of the lymph node are involved in the apoptosis phenomenon in HIV-infected lymph nodes. Apoptosis correlates with the degree of activation of the lymphoid tissue and the chronic immune activation associated with HIV infection. In late stages of HIV disease, apoptosis occurs with similar intensity but in different compartments. Apoptosis does not correlate with progression of the disease (i.e., CD4+ T-cell count) or with viral burden. All lymphocyte subsets (B and T cells, CD4+ and CD8+) have been shown to undergo apoptosis. During primary HIV infection, apoptosis correlates with the degree of activation of the lymphoid tissue but not with viral burden. The importance of cellular activation in HIV infection is underscored by the observation that cyclosporin A (CsA), inhibits HIV infection in vitro by 60% to 80%. CsA has also been shown to modulate a series of parameters during primary infection in SIV-infected monkeys. CsA administration delays onset of viremia, prevents a drop in CD4+ T cells and an increase in CD8+ T lymphocytes, increases antibody response, and decreases apoptosis intensity in lymph node. These studies may provide the basis for the development of therapeutic strategies aimed at modificaton of host factors in the pathogenesis of HIV disease.